Crohn's disease (CD) is a complex genetic disorder of chronic inflammation of the gastrointestinal tract that results in increased morbidity, mortality, risk of cancer and cost to patient and society. Twenty to 30% of patients have a CD family history and the disease is four-fold increased in persons of Ashkenazi Jewish (AJ) ancestry. Multiple low penetrance susceptibility genes have been identified and confirmed, but these in total account for only 20% of CD genetic heritability. As part of the NIDDK IBD Genetics Consortium (IBDGC) the applicant performed the first SNP, high density, whole genome linkage study, four-fold larger than any prior linkage study and the only study with adequate numbers of AJ CD pairs (919 CD pairs, 196 pairs AJ). Non-parametric linkage analysis confirmed the IBD1 locus (Lod of 4.86), and identified three additional loci with genome-wide significant linkage: a novel locus at chromosome 13q13.3 (Lod 3.98, simulated whole genome p-value of 0.01) in all CD pedigrees, and loci at chromosomes 1p35.2 and 3q29, in the AJ CD pedigrees (Lod 3.50 and 3.19, respectively and simulated genome p-values of 0.02 and 0.05, respectively). Parametric linkage analysis showed that the 13q and 3q loci follow a recessive, high penetrance mode of inheritance (H-Lod 3.3 - 10% of families linked and H-Lod 3.5, 24% of AJ families linked, respectively) and 1p followed a dominant mode (H-Lod 3.4, 38% of AJ families linked). An ancillary R01 study to identify disease alleles for these three loci is proposed. The applicant will work with the IBDGC to assemble DNA samples on the AJ CD pedigrees and the non-Jewish, chromosome 13 - linked pedigrees and/or within the top quartile of non-parametric linkage evidence. Saturation genotyping will be performed across the 2-lod confidence interval for each locus, with a total of 9000 SNPs. Alleles significantly associated with CD will be identified by using within-pedigree association analysis (independent of linkage) with the program PBAT. Association will be replicated and/or extended in 722 AJ cases and controls, 200 cases to be newly recruited by the IBDGC as part of the ancillary R01, per IBDGC-coordinated plans. Deep re-sequencing of associated genes and regions will be done, in at least 50 CD cases and 50 controls, to identify potential disease alleles. The applicant will use a bioinformatics approach to analyze re-sequencing data for functional relevance. These alleles will then be characterized for association with CD in the 859 total AJ case-control pairs. Lastly, the applicant will determine expression characteristics of genes associated, both analyzing expressed RNA and protein, and how expression correlates with the disease associated versus wildtype alleles. Identifying very high penetrance disease alleles will allow us to determine the specific cause of CD in patients with the disease alleles, and eventually how these alleles cause CD pathophysiology. These discoveries will make possible predicting persons at great risk for developing CD, the potential of preventing the disease in carriers, and the development of therapies, especially for those with CD attributed to these newly identified disease alleles. PUBLIC HEALTH RELEVANCE: Nearly 500,000 Americans, both children and adults, have Crohn's disease, and in approximately one-quarter of those affected, two or more family members have the disease. We have identified three small regions of the human genome, known as "loci," that correlate with familial Crohn's disease. With this study, we will test 9000 gene markers in these regions and identify the specific genes and, by gene sequencing, the specific DNA abnormalities that result in a significant proportion of familial Crohn's disease.